HES5 silencing is an early and recurrent change in prostate tumourigenesis

Prostate cancer is the most common cancer in men, resulting in over 10,000 deaths per year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86- 97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2ʹ′-deoxycytidine increased HES5 expression and down-regulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.